A hurricane in 1717 devastated the agricultural fields that supported the original settlement.
Construction of a stone church was begun in 1766. In 1768, when the Franciscans took over responsibility for colonial Baja California from the Jesuits, there were reportedly still some 300 Cochimí neophytes kept at Mulegé. However, by 1770, the mission was virtually deserted. The Dominicans, who succeeded the Franciscans in Baja in 1773, began rebuilding, but the population remained less than 100.
The mission ceased to function in 1828. The present church buildings have been extensively restored.